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Abstract:

The present invention relates to a compounds of formula I
##STR00001##
wherein A, Ar, R, R2, R3, R4, p, and o are as defined in the specification
and claims or to a pharmaceutically active salt thereof. The present
compounds are high potential NK-3 receptor antagonists for the treatment
of depression, pain, psychosis, Parkinson's disease, schizophrenia,
bipolar disorders, anxiety and attention deficit hyperactivity disorder
(ADHD).

Claims:

1. A compound of formula I ##STR00107## whereinA is --NR'--, --S--,
--S(O)-- or --S(O)2--;R' is hydrogen or lower alkyl;Ar is aryl or is
a five or six membered heteroaryl group containing one or two N-atoms;R
is a five or six membered heterocyclic group ##STR00108## whereinX1
is N or CH; andX2 is --N(R1)--, --CH2--, --O--, --S--,
--S(O)--, or --S(O)2--,R1 is hydrogen, lower alkyl,
S(O)2-lower alkyl, C(O)-lower alkyl, C(O)-cycloalkyl optionally
substituted by lower alkyl;with the proviso that at least one of X1
or X2 contains a heteroatom, or is a five or six membered heteroaryl
group containing one or two N-atoms, which groups are unsubstituted or
are substituted by one or two R1';whereinR1' is lower alkyl or
cyano;R2 is lower alkyl substituted by halogen, cyano or
nitro;R3 is halogen;R4 is hydrogen or lower alkyl;o is 1 or 2;
wherein when o is 2, each R2 is the same or different; andp is 1 or
2; wherein when p is 2, each R3 is the same or different;or a
pharmaceutically active salt, a racemic mixture, an enantiomer, an
optical isomer or a tautomeric form thereof.

2. The compound of claim 1 having formula I-A ##STR00109## whereinA is
--NR'--, --S--, --S(O)-- or --S(O)2--;R' is hydrogen or lower
alkyl;Ar is aryl or is a five or six membered heteroaryl group containing
one or two N-atoms;X1 is N or CH; andX2 is --N(R1)--,
--CH2--, --O--, --S--, --S(O)--, or --S(O)2--,R1 is
hydrogen, lower alkyl, S(O)2-lower alkyl, C(O)-lower alkyl,
C(O)-cycloalkyl optionally substituted by lower alkyl;with the proviso
that at least one of X1 or X2 contains a heteroatom,R2 is
lower alkyl substituted by halogen, cyano or nitro;R3 is
halogen;R4 is hydrogen or lower alkyl;o is 1 or 2; wherein when o is
2, each R2 is the same or different; andp is 1 or 2; wherein when p
is 2, each R3 is the same or different;or a pharmaceutically active
salt, a racemic mixture, an enantiomer, an optical isomer or a tautomeric
form thereof.

10. The compound of claim 1 having formula I-B ##STR00113## whereinA is
--NR'--, --S--, --S(O)-- or --S(O)2--;R' is hydrogen or lower
alkyl;Ar is aryl or is a five or six membered heteroaryl group containing
one or two N-atoms;het is a five or six membered heteroaryl group
containing one or two N-atoms, which groups are unsubstituted or are
substituted by one or two R1';whereinR1' is lower alkyl or
cyano;R2 is lower alkyl substituted by halogen, cyano or
nitro;R3 is halogen;R4 is hydrogen or lower alkyl;o is 1 or 2;
wherein when o is 2, each R2 is the same or different; andp is 1 or
2; wherein when p is 2, each R3 is the same or different;or a
pharmaceutically active salt, a racemic mixture, an enantiomer, an
optical isomer or a tautomeric form thereof.

11. The compound of claim 10 whereinhet-R1' is a six membered
heteroaryl group containing one or two N-atoms

13. A pharmaceutical composition comprising a therapeutically effective
amount of a compound of formula I ##STR00114## whereinA is --NR'--,
--S--, --S(O)-- or --S(O)2--;R' is hydrogen or lower alkyl;Ar is
aryl or is a five or six membered heteroaryl group containing one or two
N-atoms;R is a five or six membered heterocyclic group ##STR00115##
whereinX1 is N or CH; andX2 is --N(R1)--, --CH2--,
--O--, --S--, --S(O)--, or --S(O)2--,R1 is hydrogen, lower
alkyl, S(O)2-lower alkyl, C(O)-lower alkyl, C(O)-cycloalkyl
optionally substituted by lower alkyl;with the proviso that at least one
of X1 or X2 contains a heteroatom,or is a five or six membered
heteroaryl group containing one or two N-atoms, which groups are
unsubstituted or are substituted by one or two R1';whereinR1'
is lower alkyl or cyano;R2 is lower alkyl substituted by halogen,
cyano or nitro;R3 is halogen;R4 is hydrogen or lower alkyl;o is
1 or 2; wherein when o is 2, each R2 is the same or different; andp
is 1 or 2; wherein when p is 2, each R3 is the same or different;or
a pharmaceutically active salt, a racemic mixture, an enantiomer, an
optical isomer or a tautomeric form thereof and a pharmaceutically
acceptable carrier.

Description:

PRIORITY TO RELATED APPLICATION(S)

[0001]This application claims the benefit of European Patent Application
No. 09153097.2, filed Feb. 18, 2009, which is hereby incorporated by
reference in its entirety.

BACKGROUND OF THE INVENTION

[0002]The three main mammalian tachykinins, substance P (SP), neurokinin A
(NKA) and neurokinin B (NKB) belong to the family of neuropeptides
sharing the common COOH-terminal pentapeptide sequence of
Phe-X-Gly-Leu-Met-NH2. As neurotransmitters, these peptides exert
their biological activity via three distinct neurokinin (NK) receptors
termed as NK-1, NK-2 and NK-3. SP binds preferentially to the NK-1
receptor, NKA to the NK-2 and NKB to the NK-3 receptor.

[0003]The NK-3 receptor is characterized by a predominant expression in
CNS and its involvement in the modulation of the central monoaminergic
system has been shown. These properties make the NK-3 receptor a
potential target for central nervous system disorders such as anxiety,
depression, bipolar disorders, Parkinson's disease, schizophrenia and
pain (Neurosci. Letters, 2000, 283, 185-188; Exp. Opin. Ther. Patents
2000, 10, 939-960; Neuroscience, 1996, 74, 403-414; Neuropeptides, 1998,
32, 481-488).

[0004]Schizophrenia is one of the major neuropsychiatric disorders,
characterized by severe and chronic mental impairment. This devastating
disease affects about 1% of the world's population. Symptoms begin in
early adulthood and are followed by a period of interpersonal and social
dysfunction. Schizophrenia manifests as auditory and visual
hallucinations, paranoia, delusions (positive symptoms), blunted affect,
depression, anhedonia, poverty of speech, memory and attention deficits
as well as social withdrawal (negative symptoms).

[0005]For decades scientists and clinicians have made efforts with the aim
of discovering an ideal agent for the pharmacological treatment of
schizophrenia. However, the complexity of the disorders, due to a wide
array of symptoms, has hampered those efforts. There are no specific
focal characteristics for the diagnosis of schizophrenia and no single
symptom is consistently present in all patients. Consequently, the
diagnosis of schizophrenia as a single disorder or as a variety of
different disorders has been discussed but not yet resolved. The major
difficulty in the development of a new drug for schizophrenia is the lack
of knowledge about the cause and nature of this disease. Some
neurochemical hypotheses have been proposed on the basis of
pharmacological studies to rationalize the development of a corresponding
therapy: the dopamine, the serotonin and the glutamate hypotheses. But
taking into account the complexity of schizophrenia, an appropriate
multireceptor affinity profile might be required for efficacy against
positive and negative signs and symptoms. Furthermore, an ideal drug
against schizophrenia would preferably have a low dosage allowing
once-per-day dosage, due to the low adherence of schizophrenic patients.

[0006]In recent years clinical studies with selective NK1 and NK2 receptor
antagonists appeared in the literature showing results for the treatment
of emesis, depression, anxiety, pain and migraine (NK1) and asthma (NK2
and NK1). The most exciting data were produced in the treatment of
chemotherapy-induced emesis, nausea and depression with NK1 and in asthma
with NK2-receptor antagonists. In contrast, no clinical data on NK3
receptor antagonists have appeared in the literature until 2000.
Osanetant (SR 142,801) from Sanofi-Synthelabo was the first identified
potent and selective non-peptide antagonist described for the NK3
tachykinin receptor for the potential treatment of schizophrenia, which
was reported in the literature (Current Opinion in Investigational Drugs,
2001, 2(7), 950-956 and Psychiatric Disorders Study 4, Schizophrenia,
June 2003, Decision Recources, Inc., Waltham, Mass.). The proposed drug
SR 142,801 has been shown in a phase II trial as active on positive
symptoms of schizophrenia, such as altered behavior, delusion,
hallucinations, extreme emotions, excited motor activity and incoherent
speech, but inactive in the treatment of negative symptoms, which are
depression, anhedonia, social isolation or memory and attention deficits.

[0007]The neurokinin-3 receptor antagonists have been described as useful
in pain or inflammation, as well as in schizophrenia, Exp. Opinion. Ther.
Patents (2000), 10(6), 939-960 and Current Opinion in Investigational
Drugs, 2001, 2(7), 950-956 956 and Psychiatric Disorders Study 4,
Schizophrenia, June 2003, Decision Recources, Inc., Waltham, Mass.).

SUMMARY OF THE INVENTION

[0008]The present invention provides compounds of formula I

##STR00002##

wherein

A is --NR'--, --S--, --S(O)-- or --S(O)2--;

[0009]R' is hydrogen or lower alkyl;Ar is aryl or is a five or six
membered heteroaryl group containing one or two N-atoms;R is a five or
six membered heterocyclic group

##STR00003##

wherein

X1 is N or CH; and

X2 is --N(R1)--, --CH2--, --O--, --S--, --S(O)--, or
--S(O)2--,

[0010]R1 is hydrogen, lower alkyl, S(O)2-lower alkyl, C(O)-lower
alkyl, C(O)-cycloalkyl optionally substituted by lower alkyl;with the
proviso that at least one of X1 or X2 contains a heteroatom,or
is a five or six membered heteroaryl group containing one or two N-atoms,
which groups are unsubstituted or are substituted by one or two
R1';whereinR1' is lower alkyl or cyano;R2 is lower alkyl
substituted by halogen, cyano or nitro;R3 is halogen;R4 is
hydrogen or lower alkyl;o is 1 or 2; wherein when o is 2, each R2 is
the same or different; andp is 1 or 2; wherein when p is 2, each R3
is the same or different;or a pharmaceutically active salt thereof.

[0011]The invention includes all stereoisomeric forms, including
individual diastereoisomers and enantiomers of the compound of formula
(I) as well as racemic and non-racemic mixtures

[0013]The present invention provides compounds of formula I per se. It
also provides pharmaceutical compositions containing such compounds and
methods for the manufacture of such compounds and compositions. The
invention further provides methods for the control or prevention of
illnesses such as depression, pain, bipolar disorders, psychosis,
Parkinson's disease, schizophrenia, anxiety and attention deficit
hyperactivity disorder (ADHD).

[0019]The term "cycloalkyl" denotes a saturated carbon ring containing
from 3-6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl
or cyclohexyl and the like.

[0020]The term "aryl" denotes a cyclic aromatic hydrocarbon radical
consisting of one or more fused rings containing 6-14 carbon atoms in
which at least one ring is aromatic in nature, for example phenyl,
naphthyl, 1,2,3,4-tetrahydronaphthalenyl or indanyl. Preferred is the
phenyl group.

[0021]The term "five or six membered heteroaryl" denotes a cyclic aromatic
radical consisting of one or more fused rings containing 5-14 ring atoms,
preferably containing 5-10 ring atoms, in which at least one ring is
aromatic in nature and which contains at least one heteroatom selected
from N, for example quinoxalinyl, dihydroisoquinolinyl, pyrazin-2-yl,
pyrazolyl, 2,4-dihydro-pyrazol-3-one, pyridinyl, isoxazolyl, pyridyl,
pyrimidin-4-yl, pyrimidin-5-yl, [1,2,4]triazol-1-yl,
[1,6]naphthyridin-2-yl, tetrazolyl, thiazolyl, imidazol-1-yl, Preferred
heteroaryl group is pyridine-2, 3 or 4-yl or pyrimidinyl.

[0022]The term "five or six membered heterocyclyl" ring denotes a five or
six membered non-aromatic ring containing one or two heteroatoms selected
from N, S and O, for example the following groups: morpholinyl,
[1,4]diazepam-1-yl, piperazinyl, pyrrolidinyl, piperidin-1-yl,
tetrahydrofuranyl, tetrahydrothiophenyl, piperidin-4-yl or
1,1-dioxo-λ6-thiomorpholinyl.

[0023]"Pharmaceutically acceptable," such as pharmaceutically acceptable
carrier, excipient, etc., means pharmacologically acceptable and
substantially non-toxic to the subject to which the particular compound
is administered.

[0025]"Therapeutically effective amount" means an amount that is effective
to prevent, alleviate or ameliorate symptoms of disease or prolong the
survival of the subject being treated.

[0026]In one embodiment, compounds of formula I are those of formula I-A,

##STR00004##

wherein the definitions are as described above and

X1 is N or CH;

X2 is --N(R1)--, --CH2--, --O--, --S--, --S(O)--,
--S(O)2--,

[0027]R1 is hydrogen, lower alkyl, S(O)2-lower alkyl, C(O)-lower
alkyl, C(O)-cycloalkyl optionally substituted by lower alkyl;with the
proviso that at least one of X1 or X2 is a heteroatom.

[0028]In another embodiment, compounds of formula I are further those of
formula I-B,

##STR00005##

wherein het is a five or six membered heteroaryl group containing one or
two N-atoms, which groups are unsubstituted or are substituted by one or
two R1' and wherein R1' is lower alkyl or cyano, and the other
definitions are as described above.

[0029]In detail, preferred are compounds of formula I-A are those wherein

[0077]The preparation of compounds of formula I of the present invention
can be carried out in sequential or convergent synthetic routes.
Syntheses of the compounds of the invention are shown in the following
schemes. The skills required for carrying out the reaction and
purification of the resulting products are known to those skilled in the
art. The substituents and indices used in the following description of
the processes have the significance given herein before unless indicated
to the contrary.

[0078]The compounds of formula I can be manufactured by the methods given
below, by the methods given in the examples or by analogous methods.
Appropriate reaction conditions for the individual reaction steps are
known to a person skilled in the art. The reaction sequence is not
limited to the one displayed in the schemes, however, depending on the
starting materials and their respective reactivity the sequence of
reaction steps can be freely altered. Starting materials are either
commercially available or can be prepared by methods analogous to the
methods given below, by methods described in references cited in the
description or in the examples, or by methods known in the art.

[0079]The present compounds of formula I and their pharmaceutically
acceptable salts can be prepared by methods, known in the art, for
example by the process variant described below, which process comprises

a) coupling a compound of formula

##STR00009##

to produce a compound of formula

##STR00010##

wherein the definitions are described above, orb) oxidizing a compound of
formula

##STR00011##

to produce a compound of formula

##STR00012##

wherein the definitions are described above, orc) coupling a compound of
formula

##STR00013##

with hal-(R2)o to produce a compound of formula

##STR00014##

wherein the definitions are described above, ord) coupling a compound of
formula

[0082]To a stirred solution of a carboxylic acid derivative (commercially
available or known in the literature) (1 mmol) in 10 mL of
CH2Cl2 was added (1.3 mmol) of EDC, (1.3 mmol) of HOBt and
Et3N (1.3 mmol). After one hour at RT, was added a corresponding
pyrrolidine intermediate. The mixture was stirred at RT over night and
then poured onto water and extracted with CH2Cl2. The combined
organic phases were dried over Na2SO4 and concentrated under
vacuo. Flash chromatography or preparative HPLC afforded the title
compound.

General Procedure II

Coupling Between a Compound of Formula V, XI, XVI, XXII, XXX, XXXVI,
XXXVIII, XLVII or LVI and an Acid Chloride or Carbamoyl Chloride

[0083]A solution of the pyrrolidine (1 mmol) of formula (v.s.) in
CH2Cl2 (10 mL) was treated with Et3N (1.2 mmol) and an
acid chloride or carbamoyl chloride (1.2 mmol) and stirred at RT
overnight. The reaction mixture was then poured onto water and extracted
with CH2Cl2. The combined organic phases were dried over
Na2SO4 and concentrated under vacuo. Purification by
preparative HPLC yielded the title compound.

General Procedure III

[0084]Nucleophilic Substitution Reaction: Coupling Between a Compound of
Formula VIII with Thiophenyl and Thiopyridone

[0085]To a stirred solution of tosylate VIII (1 mmol) and potassium
carbonate (3 mmol) in DMF (5 mL) at RT were added a thiophenol derivative
(3 mmol). Stirring was continued for 1.5 h at 100° C. The reaction
mixture was washed with H2O and the organic phase was dried over
Na2SO4. Column chromatography yielded the title compound.

[0087]A solution of amine XIII or XIV (1 mmol), triethylamine (0.4 mL, 2
mmol) and a heteroaromatic chloride (1 mmol) in DMSO (0.5 mL) in a high
pressure glass vial is heated at 150-160° C. for several hours,
depending on the nature of the compound. After the reaction ran to
completion it was diluted with water, extracted with ethyl acetate and
the combined organic phases were dried over sodium sulfate. Column
chromatography yielded the title compound.

General Procedure V

[0088]Cleavage of the N-Benzyl Group with 1-chloroethylchloroformat and
Methanol

[0089]N-Benzyl pyrrolidine derivatives (2 mmol) were dissolved in toluene
(10 mL) and treated with NEt(iProp)2 (6 mmol) and
1-chloroethylchloroformat (6 mmol) at 100° C. for 1.5 h. The
solvent was evaporated, the residue taken up in MeOH (15 mL) and heated
to reflux for 3 h. After evaporation of the solvent the residue was
subjected to column chromatography to yield the de-benzylated product.

[0091]To a stirred solution of tosylate XIX (1 mmol) and potassium
carbonate (3 mmol) in DMF (5 mL) at RT were added an anilin derivative of
formula (3 mmol). Stirring was continued for several hours, depending on
the nature of the aniline derivative, at 120° C. The solvent was
evaporated and the residue taken up in ethyl acetate. After washing with
H2O the organic phase was dried over Na2SO4, filtered and
concentrated. Column chromatography of the residue yielded the title
compound.

##STR00018## ##STR00019##

X is halogen and the other definitions are as described above.

[0092]The 3,4-disubstituted pyrrolidines IV were prepared via a stereo
specific 1,3-dipolar cycloaddition between the (E)-3-substituted
phenyl-acrylic acid ethyl ester derivatives II and the azomethine glide
generated in situ from the
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine III in
the presence of a catalytic amount of acid, such as TFA. Selective
N-debenzylation was then carried out using several known procedures which
are compatible with the substitution patterns of the aromatic ring to
afford V. A coupling with a suitable acid chloride, carboxylic acid or
carbamoyl chloride using known methods gave VI. Reduction of the ester
moiety using standard conditions for example LiBH4 yielded the
alcohol VII. Reaction with p-toluolsulfonyl chloride gave the tosylat
VIII which was then displaced by thiophenol derivatives and if desired
oxidized with mCPBA to yield sulfones.

[0095]To a solution of
(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic acid
ethyl ester (2.50 g, 6.61 mmol) in CH3CN (55 mL) was added
2,2,2-trichloroethyl chloroformate (1.34 mL, 9.91 mmol) and stirring was
continued for 4 hours at RT. Volatiles were removed under vacuo, and the
residue was dissolved in AcOH (25 mL). Then Zn dust (1.20 g) was added
portion wise. After three hours at RT the reaction mixture was filtered
on celite, the solvent removed under vacuo followed by an extraction with
EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on
Na2SO4 and column chromatography (SiO2,
CH2Cl2/MeOH 9:1) yielded 1.85 g (97%) of the title compound as
a light yellow oil. ES-MS m/e: 288.1 (M+H.sup.+).

[0127]A solution of
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (10.25
g, 43 mmol) in CH2Cl2 (55 mL) was added dropwise, over a 30
minutes period, to a stirred solution of
(E)-3-(3,4-dichloro-phenyl)-acrylnitrile (5.70 g, 29 mmol) and
trifluoroacetic acid (0.22 mL, 3 mmol) in CH2Cl2 (10 mL) at
0° C. The ice bath was removed, and the solution was stirred at
25° C. for an additional 48 h. It was then concentrated and
purification by flash chromatography (SiO2, CH2Cl2)
afforded the title compound (7.0 g, 73%) as a colorless oil. ES-MS m/e:
332.3 (M+H.sup.+).

b) (3SR,4RS)-4-(3,4-Dichloro-phenyl)-pyrrolidine-3-carbonitrile

[0128]To a solution of
(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonitrile
(2.0 g, 6.6 mmol) dissolved in CH3CN (30 mL) was added
2,2,2-trichloroethyl chloroformate (1.22 mL, 9.91 mmol) and stirring was
continued for 4 hours at RT. Volatiles were removed under vacuo, and the
residue was dissolved in AcOH (25 mL) before a total of 1.20 g of Zn dust
was added portion wise. After three hours at RT, the reaction mixture was
filtered on celite, the solvent removed under vacuo, followed by an
extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were
dried on Na2SO4 and the crude reaction product obtained used in
the next reaction step, yielding 0.6 g (55%) of the title compound as a
light yellow oil. ES-MS m/e: 242.1 (M+H.sup.+).

[0130]To a stirred solution of
(3SR,4RS)-4-(3,4-Dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbo-
nyl)-pyrrolidine-3-carbonitrile (0.1 g, 0.23 mmol) in tetrahydrofuran (1.0
mL) at 0° C. was added BH3 in tetrahydrofuran (0.55 mL, 0.55
mmol). After 2 hours of stirring at ambient temperature the reaction
mixture was quenched with MeOH and the volatiles were removed under
vacuo. The residue was taken up in H2O, extracted with EtOAc and the
combined organic phases were dried over Na2SO4. Flash
chromatography (SiO2, EtOAc, then CH2Cl2/MeOH 19:1)
yielded the title product (0.57 g, 56%) as a colorless oil. ES-MS m/e:
436.1 (M+H.sup.+).

[0135]To a stirred solution of
(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carbonitrile (13
g, 0.39 mol) in tetrahydrofuran (250 mL) at 0° C. was added
portion-wise LiAlH4 (1.56 g, 0.41 mol). After 2 hours of stirring at
0° C. the reaction mixture was quenched with water (50 mL) and 5N
aqueous NaOH (12 mL) and stirred 30 min. The residue was extracted with
EtOAc and the combined organic phases were dried over Na2SO4,
filtered and the volatiles removed under vacuo to yield the crude title
product (12.5 g, 95%) as a yellow oil which was used directly in the next
reaction steps. ES-MS m/e: 336.4 (M+H.sup.+).

[0182](3SR,4RS)-{3-(3,4-Dichloro-phenyl)-4-[(5-trifluoromethyl-pyridin-2-y-
lamino)-methyl]-pyrrolidin-1-yl}-(4-methanesulfonyl-piperazin-1-yl)-methan-
one (75 mg, 0.13 mmol) were dissolved in DMF (2 mL) and treated with NaH
(55% dispersion in oil) (6.0 mg, 0.14 mmol) at ambient temperature. After
5 min methyl iodide (0.01 mL, 0.14 mmol) was added and the reaction
mixture was stirred over night. After quenching with water and extraction
with ethyl acetate (3×10 mL) the combined organic phases were dried
on sodium sulfate and filtered. After evaporation of the solvent the
crude product was subjected to column chromatography (silica gel, ethyl
acetate) to yield the title product (66%) as a light yellow oil. ES-MS
m/e: 594.2 (M+H.sup.+).

[0218]1-(1-Methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid ethyl
ester (6.34 g, 26.5 mmol) and LiOH (1.67 g, 39.7 mmol) were stirred in a
mixture of ethanol (30 mL), THF (30 mL) and water (15 mL) for 90 min at
ambient temperature. After evaporation of the volatiles the residue was
taken up in dichloro methane and extracted with 1N HCl. The organic phase
was dried over sodium sulfate, filtered and evaporated to yield the title
product (4.8 g, 86%) as colorless solid.

[0231](3SR,4RS) 1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic
acid ethyl ester (3.6 g, 0.01 mol) were dissolved in THF (70 mL). At
0° C. LiAlH4 (0.38 g, 0.01 mol) was added portion wise. After
stirring at 0° C. for 4 h water (3 mL), then 5N NaOH (3 mL) and
additional water (9 mL) was added. After stirring at ambient temperature
for 30 min the mixture was extracted with ethyl acetate (3×10 mL),
the combined organic phases were dried on sodium sulfate, filtered and
evaporated. The crude title product was obtained as a light yellow oil
(3.0 g, 94%) and directly used in the next step.

[0344]A solution of
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (32.78
g, 0.138 mol) in CH2Cl2 (50 mL) was added drop wise, over a 30
minutes period, to a stirred solution of
(E)-4-(3,4-dichloro-phenyl)-but-3-en-2-one (CAS RN: 55420-70-7) (19.80 g,
0.092 mol) and trifluoroacetic acid (1.05 mL, 0.009 mol) in
CH2Cl2 (100 mL) at 0° C. The ice bath was removed, and
the solution was stirred at 25° C. for an additional 48 h. It was
then concentrated and purification by flash chromatography (SiO2,
CH2Cl2/MeOH 98:2) afforded the title compound (28.3 g, 88%) as
a yellow oil. ES-MS m/e: 348.2 (M+H.sup.+).

b) 1-[(3SR,4RS)-4-(3,4-Dichloro-phenyl)-pyrrolidin-3-yl]-ethanone

[0345]To a solution of
1-[(3SR,4RS)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethanone
4.00 g (9.20 mmol) dissolved in CH3CN (50 mL) was added 2.48 mL
(18.40 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was
continued for 3 hours at RT. Volatiles were removed under vacuo, and the
residue was dissolved in AcOH (30 mL) before a total of 1.5 g of Zn dust
was added portion wise. After three hours at RT, the reaction mixture was
filtered on celite, the solvent removed under vacuo, followed by
extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were
dried on Na2SO4 and column chromatography (SiO2,
CH2Cl2/MeOH 9:1 to 8:2) yielded the title compound (1.50 g,
63%) as a colorless oil. ES-MS m/e: 258.0 (M+H.sup.+).

[0462]A solution of
N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (201.6
g, 849 mmol) in CH2Cl2 (600 mL) was added dropwise over a 30
minutes period to a stirred solution of 3-(4-chlorophenyl)-2-propionic
acid ethyl ester (125.9 g, 566 mmol) and trifluoroacetic acid (4.3 mL,
114 mmol) in CH2Cl2 (400 mL) at 0° C. The ice bath was
removed, and the solution was stirred at 25° C. for an additional
4 h. It was then concentrated and the reaction mixture was taken up in
dioxane (1.2 L). Then 1N NaOH (146 mL) were added and the mixture was
stirred at ambient temperature for 72 h. The volatiles were removed and
the residue was extracted with TBDME and water. The organic phases were
extracted with water and the combined aqueous phases were acidified with
aqueous HCl (10%). Upon stirring at ambient temperature over night a
precipitation formed which was isolated, washed with water and ethanol
and dried under high vacuum to yield the title product (148 g, 76%) as a
colorless solid. ES-MS m/e: 314.8 (M+H.sup.+).

b) (3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid

[0463]A 185-ml stainless steel autoclave was charged under argon in a
glove box (O2 content<2 ppm) with
1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid
(5.00 g, 15.1 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP] (3.8 mg, 5.0
μmol) (S/C 5'000) and methanol (150 mL). The asymmetric hydrogenation
was run under 40 bar of hydrogen for 20 h at 30° C. and additional
2 h at 60° C. to complete the conversion (>99.6% conversion and
99.9% ee). After the pressure was released, the white suspension was
stirred at 0-5° C. for 2 h, filtered off and the filter cake was
washed with cold (0-5° C.) methanol (20 mL) and dried under vacuum
at room temperature to yield the title product (4.75 g, 99%) with 99%
purity and 99.9% ee. ES-MS m/e: 316.1 (M+H.sup.+).

[0464](3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid
(7.0 g, 22.0 mmol) were dissolved in methanol (75 mL) and at ambient
temperature treated with sulfuric acid 97% (2.4 mL). The reaction mixture
was stirred at 60° C. for 18 h. At 0° C. dichloro methane
(150 mL) was added followed by aqueous sodium carbonate 10% (150 mL)
(final pH 11) under vigorous stirring. The phases were separated. The
aqueous phase was washed with dichloro methane, the combined organic
phases with water and brine and then dried on sodium sulfate. After
filtration and evaporation of the solvent the title product was obtained
as a light brown oil (7.0 g, 96%) which was directly used in the next
step. ES-MS m/e: 330.8 (M+H.sup.+).

[0469]Toluene-4-sulfonic acid
(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-ylmethyl ester (4.0 g,
0.009 mmol) were dissolved in a 2.0 M solution of MeNH2 in THF (31
mL) in an autoclave and heated to 80° C. over night. The volatiles
were removed and the crude product subjected to column chromatography
(silica gel, heptane/ethyl acetate 1:1) to yield the title compound (2.25
g, 81%) as a colorless oil.

[0539](3S,4S)-1-Benzyl-4-(3,4-dichloro-phenyl)-pyrrolidine-3-carboxylic
acid (CAS RN: 907184-53-6) (35.7 g, 0.102 mol) were dissolved in methanol
(350 mL) and at ambient temperature treated with sulfuric acid 97% (10.9
mL). The reaction mixture was stirred at 60° C. for 18 h. At
0° C. dichloro methane (500 mL) was added followed by aqueous
sodium carbonate 10% (500 mL) (final pH 11) under vigorous stirring. The
phases were separated. The aqueous phase was washed with dichloro
methane, the combined organic phases with water and brine and then dried
on sodium sulfate. After filtration and evaporation of the solvent the
title product was obtained as a yellow oil (36.3 g, 98%) which was
directly used in the next step. ES-MS m/e: 365.3 (M+H.sup.+).

[0546]Toluene-4-sulfonic acid
(3R,4S)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-ylmethyl ester (2.0
g, 0.004 mmol) were dissolved in 2.0 M solution of EtNH2 in THF (14
mL) in an autoclave and heated to 80° C. over night. The volatiles
were removed and the crude product subjected to column chromatography
(silica gel, heptane/ethyl acetate 1:1) to yield the title compound (1.2
g, 81%) as a yellow oil.

[0634]As mentioned earlier, the compounds of formula I and their
pharmaceutically usable addition salts possess valuable pharmacological
properties Compounds of the present invention are antagonists of
neurokinin 3 (NK-3) receptors. The compounds were investigated in
accordance with the tests given hereinafter.

Experimental Procedure

[0635]The compounds were investigated in accordance with the tests given
hereinafter

[3H]SR142801 Competition Binding Assay

[0636]hNK3 receptor binding experiment were performed using
[3H]SR142801 (Catalog No. TRK1035, specific activity: 74.0 Ci/mmol,
Amersham, GE Healthcare UK limited, Buckinghamshire, UK) and membrane
isolated from HEK293 cells transiently expressing recombinant human NK3
receptor. After thawing, the membrane homogenates were centrifuged at
48,000×g for 10 min at 4° C., the pellets were resuspended
in the 50 mM Tris-HCl, 4 mM MnCl2, 1 μM phosphoramidon, 0.1% BSA
binding buffer at pH 7.4 to a final assay concentration of 5 μg
protein/well. For inhibition experiments, membranes were incubated with
[3H]SR142801 at a concentration equal to KD value of
radioligand and 10 concentrations of the inhibitory compound (0.0003-10
μM) (in a total reaction volume of 500 μA) for 75 min at room
temperature (RT). At the end of the incubation, membranes were filtered
onto unitfilter (96-well white microplate with bonded GF/C filter
preincubated 1 h in 0.3% PEI+0.3% BSA, Packard BioScience, Meriden,
Conn.) with a Filtermate 196 harvester (Packard BioScience) and washed 4
times with ice-cold 50 mM Tris-HCl, pH 7.4 buffer. Nonspecific binding
was measured in the presence of 10 μM SB222200 for both radioligands.
The radioactivity on the filter was counted (5 min) on a Packard
Top-count microplate scintillation counter with quenching correction
after addition of 45 μl of microscint 40 (Canberra Packard S. A.,
Zurich, Switzerland) and shaking for 1 h. Inhibition curves were fitted
according to the Hill equation: y=100/(1+(x/IC50)nH), where
nH=slope factor using Excel-fit 4 software (Microsoft). IC50
values were derived from the inhibition curve and the affinity constant
(Ki) values were calculated using the Cheng-Prussoff equation
Ki=IC50/(1+[L]/KD) where [L] is the concentration of
radioligand and KD is its dissociation constant at the receptor,
derived from the saturation isotherm. All experiments were performed in
duplicate and the mean±standard error (SEM) of the individual Ki
values was calculated.

[0637]Results of some compounds with a hNK-3 receptor affinity <0.10
μM are shown in the following table 1.

[0638]The present invention also provides pharmaceutical compositions
containing compounds of the invention, for example, compounds of formula
I or pharmaceutically acceptable salts thereof and a pharmaceutically
acceptable carrier. Such pharmaceutical compositions can be in the form
of tablets, coated tablets, dragees, hard and soft gelatin capsules,
solutions, emulsions or suspensions. The pharmaceutical compositions also
can be in the form of suppositories or injectable solutions.

[0639]The pharmaceutical compositions of the invention, in addition to one
or more compounds of the invention, contain a pharmaceutically acceptable
carrier. Suitable pharmaceutically acceptable carriers include
pharmaceutically inert, inorganic or organic carriers.
gelatingelatinLactose, corn starch or derivatives thereof, talc, stearic
acid or its salts etc can be used as such excipients e.g. for tablets,
dragees and hard gelatin capsules.

[0645]The dosage at which compounds of the invention can be administered
can vary within wide limits and will, of course, be fitted to the
individual requirements in each particular case. In general, in the case
of oral administration a daily dosage of about 10 to 1000 mg per person
of a compound of general formula I should be appropriate, although the
above upper limit can also be exceeded when necessary.

Example A

[0646]Tablets of the following composition are manufactured in the usual
manner:

[0648]The active substance, lactose and corn starch are firstly mixed in a
mixer and then in a comminuting machine. The mixture is returned to the
mixer, the talc is added thereto and mixed thoroughly. The mixture is
filled by machine into hard gelantine capsules.

[0650]The suppository mass is melted in a glass or steel vessel, mixed
thoroughly and cooled to 45° C. Thereupon, the finely powdered
active substance is added thereto and stirred until it has dispersed
completely. The mixture is poured into suppository moulds of suitable
size, left to cool, the suppositories are then removed from the moulds
and packed individually in wax paper or metal foil.

Patent applications by Anja Limberg, Basel CH

Patent applications by Claus Riemer, Freiburg DE

Patent applications by Hasane Ratni, Habsheim FR

Patent applications by Henner Knust, Rheinfelden DE

Patent applications in class The additional hetero ring is a diazine

Patent applications in all subclasses The additional hetero ring is a diazine